Download Introduction to Targeted Therapy

Introduction to Targeted Therapy
Cancer remains the second leading cause of death in the United States, despite the significant
advances in cancer therapy made over the past several decades. Many factors contribute to our
limited success in fighting cancer. Late diagnosis, often after the cancer has already spread to
distant locations, is certainly a major reason why many patients are incurable. Equally problematic
are the limitations of our current therapeutic armamentarium. The modern-day approach to cancer
management is a multidisciplinary one, consisting
primarily of surgery, radiation therapy and chemotherapy, in varying combinations. However, any
approach is only as good as its components. All three of these treatments function within a limit
called the "therapeutic window". This concept refers to the ability of a treatment to kill cancer cells
while minimizing the toxicity to healthy, normal cells. Every surgical procedure, radiation course,
and chemotherapy agent is bound by this window, and can not exceed it without causing undue
harm to the patient. Thus, conventional therapies of today can only achieve so much success in the
fight against cancer.
Naturally, physicians and scientists are vigorously investigating ways in which to improve the efficacy
of
these treatment modalities. This includes things like modifying surgical techniques, refining
radiation delivery methods (e.g.: see IMRT and Proton Therapy), and developing new
chemotherapy agents. These efforts certainly help, but ultimately, there is still room for
improvement. Both surgery and radiation therapy have often been described as physical solutions to
a biological problem. Chemotherapy, often the cornerstone of treatment in advanced and palliative
cases, can be viewed as more of a chemical solution to a biological problem. From the ongoing
quest to improve our therapeutic arsenal, a newer, fourth weapon has emerged in the fight against
cancer: targeted therapies. This is an ever-growing and exciting new field of research and
development. This section will attempt to describe targeted therapies in general, and then take a
closer look at some specific types of targeted agents. Many of these have received much publicity
recently, and will undoubtedly revolutionize the future of clinical cancer trials and research.
What is targeted therapy?
Targeted therapy is a general term that refers to a medication or drug that targets a specific
pathway in the growth and development of a tumor. By attacking or blocking these important
targets, the therapy helps to fight the tumor itself. The targets themselves are typically various
molecules (or small particles) in the body that are known or suspected to play a role in cancer
formation.
How are targeted therapies named?
The names of the major classes of targeted therapies typically include the word "anti-", or
"inhibitor", together with the name of the target itself. This means that the drug blocks, (is "anti"),
that particular target. Then within each class of inhibitors, there is/are the actual drug(s).
It is important to realize that a single drug can have several names, including a generic name
and a brand name, which can differ in various parts of the world. This can be confusing
because often the generic and brand names are used interchangeably in the literature and the
media. Throughout this educational section, we will use primarily the generic name of the
drug.
What are the different classes of targeted therapy? In other words, what are the different targets?
There are a number classes of targeted therapies, with new potential targets being discovered
all the time. Let’s review a few of the major classes and some of the medications in those
categories.
I) Tyrosine kinase receptor inhibitors
A tyrosine kinase receptor is a molecular structure or site on the surface of a cell that binds with
substances such as hormones, antigens, drugs, or neurotransmitters. When it binds with one of
these triggering substances, the receptor performs a chemical reaction, which in turn triggers a
series of reactions inside the cell. These reactions include cell multiplication, death, maturation,
and migration. In tumor cells, all of these reactions are critical for the tumor to survive, thrive and
spread throughout the body. By blocking the receptor, the goal is to prevent the cascade of
reactions and prevent tumor survival.
There are many different types of tyrosine kinase receptors in the body. One family of tyrosine
kinase receptors is called the human epidermal receptor family, or the HER family. The members
of the family are:
HER1 (also called the Epidermal Growth Factor Receptor or EGFR) HER2 (also called ErbB2 or
HER2/neu), HER3 (also called ErbB3), HER4 (also called ErbB4), The first 2 family members, EGFR
and HER2/neu, are the two most extensively studied targets in oncology.
A) EGFR inhibitors
Within this group, there are two types of inhibitors, small molecule inhibitors and antibody inhibitors.
Small Molecule inhibitors
Brand Name Generic Name Lab Development Name
Iressa
Gefitinib
ZD1839
Tarceva
Erlotinib
OSI 771
Antibody inhibitors
Brand Name Generic Name Lab Development Name
Cetuximab
C225
Erbitux
B) HER2/neu inhibitors
Brand Name Generic Name Lab Development Name
Herceptin
Trastuzumab NO 34
GW572016
Tykerb
Lapatinib
*this drug targets
HER2/neu and EGFR
C) Bcr-abl inhibitors
Another group of tyrosine kinase inhibitors inhibit the bcr-abl tyrosine kinase, which is
formed in certain types of leukemia.
Brand Name Generic Name
Lab Development Name
Imatinib mesylate STI 571
Gleevec
Sprycel
Dasatinib
BMS-354825
II) Angiogenesis inhibitors
Tumor cells, like normal cells, need an adequate blood supply in order to perform vital cellular
functions. In fact, as cells multiply and grow in number and size, access to nutrients and blood
supply becomes increasingly critical for their continued survival. Actively dividing tumors secrete
special proteins that signal the surrounding area to sprout new blood vessels. This new blood vessel
formation is called angiogenesis, and the proteins that trigger this process are called pro-angiogenic
factors. The main pro-angiogenic factor is VEGF, which stands for vascular endothelial growth
factor. In essence, by secreting VEGF and other related proteins to stimulate new blood vessel
growth, tumors support and feed themselves, allowing them to grow. The concept behind
angiogenesis inhibition, then, is to thwart this process and thereby fight tumor progression.
Brand Name Generic Name Lab Development Name
Avastin
Bevacizumab anti-VEGF
III) Proteasome inhibitors
The proteasome is a structure inside the cell, which breaks down proteins that have been labeled
to undergo degradation and recycling. This process is important because it removes possibly
damaged or defective proteins. But more importantly, it is a required process for normal
regulation of cellular growth, division, angiogenesis, death, etc.
By binding part of the proteasome, a drug can inhibit the breakdown of some of these proteins that
have been marked for destruction. This "wreaks havoc" in a sense, and can result in growth arrest
or death of the cell. In fact, and fortunately, this tends to happen more so in cancer cells than in
normal cells.
For those of you who would like more detail, here's a specific example of how this effect works
to control tumors:
NF-kappa-B is a protein found in both normal and tumor cells. It is typically inactive because it is
bound by another protein called inhibitor of kappa B (I-kappa B)-alpha. When this inhibitor
protein is broken down by proteasomes, the NF-kappa-B is now active and can travel to the
nucleus where DNA lives. Once there, the active NF-kappa-B starts a chain of events that can
promote tumor growth and spread. A drug that inhibits the proteasome can block the breakdown of
inhibitor I-kappa-B-alpha, and thus block activation of NF-kappa-B. The result is a block of
growth factors in the tumor cell.
Brand Name Generic Name Lab Development Name
Velcade
Bortezomib
PS-341
IV) Immunotherapy
The classes of targeted therapies described above all bind to and block specific targets, thereby
disrupting the chain of events needed for tumor cell proliferation. In contrast, targeted
immunotherapy agents bind to their targets, not to interfere with growth signals, but rather to
trigger immune signals. By binding specific protein particles (antigens) that are found on the
surface certain types of cancer cells, targeted immunotherapy agents can lead to a series of antitumor immune reactions in the body, ultimately causing the tumor cell to die. Furthermore, if these
immunotherapy drugs are chemically attached to radioactive substances, you could launch a dual
attack on the tumor cells, taking advantage of both the anti-tumor immune response and the antitumor radiation reaction.
Targeted immunotherapy drugs are essentially a collection of monoclonal antibodies, all of which
have different targets. Antibodies are proteins that seek out and bind to specific antigens; every
antibody has a particular antigen with which it "fits". Antibodies are named for the antigen that they
bind, e.g.: the anti-CD20 antibody binds to the antigen CD20.
The term monoclonal means that a group of antibodies all came from one master cell.
In other words, they are clones all derived from one cell line. When there is a radioactive substance
(radioisotope) attached, these drugs are called radioimmunotherapy agents.
Brand Name
Rituxan,
MabThera
Generic Name Lab Development Name
Rituximab
anti-CD20
Bexxar
Tositumomab
I-131-radiolabelled antiCD20
Zevalin
Ibritumomab
Y-90-radiolabelled anti-CD20
V) Other types
Brand Name Generic Name
Lab Development Name
Gleevec
Imatinib mesylate STI 571